title: EZH2 protein expression associates with the early pathogenesis, tumor progression, and prognosis of non-small cell lung carcinoma.
abstract: OBJECTIVE
  Enhancer of zeste homolog 2 (EZH2) promotes carcinogenesis by epigenetically silencing tumor suppressor genes. We studied EZH2 expression by immunohistochemistry in a large series of non-small cell lung carcinomas (NSCLC) in association with tumor characteristics and patient outcomes.
  
  
  METHODS
  EZH2 immunohistochemistry expression was analyzed in 265 normal and premalignant bronchial epithelia, 541 primary NSCLCs [221 squamous cell carcinomas (SCC) and 320 adenocarcinomas] and 36 NSCLCs with paired brain metastases. An independent set of 91 adenocarcinomas was also examined. EZH2 expression was statistically correlated with clinico-pathological information, and EGFR/KRAS mutation status.
  
  
  RESULTS
  EZH2 expression was significantly (P < 0.0001) higher in SCCs compared with adenocarcinomas and in brain metastasis relative to matched primary tumors (P = 0.0013). EZH2 expression was significantly (P < 0.0001) elevated in bronchial preneoplastic lesions with increasing severity. In adenocarcinomas, higher EZH2 expression significantly correlated with younger age, cigarette smoking, and higher TNM stage (P = 0.02 to P < 0.0001). Higher EZH2 expression in adenocarcinoma was associated with worse recurrence-free survival (RFS; P = 0.025; HR = 1.54) and overall survival (OS; P = 0.0002; HR = 1.96). Furthermore, lung adenocarcinomas with low EZH2 levels and high expression of the lineage-specific transcription factor, TTF-1, exhibited significantly improved RFS (P = 0.009; HR = 0.51) and OS (P = 0.0011; HR = 0.45), which was confirmed in the independent set of 91 adenocarcinomas.
  
  
  CONCLUSIONS
  In lung, EZH2 expression is involved in early pathogenesis of SCC and correlates with a more aggressive tumor behavior of adenocarcinoma. When EZH2 and TTF-1 expressions are considered together, they serve as a prognostic marker in patients with surgically resected lung adenocarcinomas.
authors.affiliation: Authors' Affiliations: Departments of Thoracic/Head and Neck Medical Oncology, Pathology, Biostatistics, Thoracic Surgery, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and The University of Ottawa, Ottawa, Canada.
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Solis
authors.forename: Heather
authors.initials: H
authors.lastname: Lin
authors.forename: Ping
authors.initials: P
authors.lastname: Yuan
authors.forename: Ximing
authors.initials: X
authors.lastname: Tang
authors.forename: Humam
authors.initials: H
authors.lastname: Kadara
authors.forename: Erick
authors.initials: E
authors.lastname: Riquelme
authors.forename: Hector
authors.initials: H
authors.lastname: Galindo
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Moran
authors.forename: Neda
authors.initials: N
authors.lastname: Kalhor
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Swisher
authors.forename: George R
authors.initials: GR
authors.lastname: Simon
authors.forename: David J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000201:enzymology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D008297:Male; D015999:Multivariate Analysis; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D012372:ROC Curve; D014157:Transcription Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2